PROJECT SUMMARY Type 2 diabetes (T2D) is an epidemic of our time afflicting more than 400 million people globally. Identification of novel preventable risk factors is urgent because established risk factors do not fully account for the rapid increase in T2D rates. The etiologic role of heavy metals in T2D risk has gained considerable attention worldwide. In the U.S., the National Toxicological Program recently recommended further research on this topic following a comprehensively review of the relationship between environmental factors and T2D. Recent data linking heavy metals to T2D risk, while tantalizing, come mainly from cross-sectional studies susceptible to reverse causation. Moreover, few studies have investigated the role of exposures to multiple metals on T2D risk, such that there is little evidence of the independent and joint effects of multiple metals. Separately, essential metals are recommended as beneficial supplements to mitigate the diabetic effects of toxic metals, but the optimal levels of essential metals required to counteract the toxic metal effects are not well understood. Thus, large and high-quality prospective studies are urgently needed to further investigate heavy metals as risk factors for T2D, and the possible mitigating role of essential metals. Our research team, with support from NIH, has built the population-based prospective Jinchang Metal Cohort Study. This on-going study includes in- person interviews of 42,122 participants in 2011-13, a first follow-up visit in 2014-16, and a second follow-up visit started in 2017. At the baseline and subsequent visits, subjects completed 1) physical examinations; 2) clinical laboratory tests; 3) in-person interviews; and 4) collections of blood and urine samples. Extensive pilot work on T2D risk associated with metal exposure has already been conducted in this population. With such extensive data available from this large prospective population-based cohort, we are now in a unique position to conduct a nested case-control study to comprehensively investigate if heavy metal exposures increase T2D risk. Baseline serum and urine levels of selected heavy metals will be measured from 2,200 incident T2D cases and their individually age-sex-matched 2,200 controls who were T2D- and prediabetes-free at the time when the corresponding cases were diagnosed with T2D. The study specific aims include: 1) Determine whether baseline toxic metal levels are independently or jointly associated with T2D risk; 2) Determine whether imbalanced baseline levels (deficiency or overexposure) of essential metals are independently or jointly associated with T2D risk; and 3) Determine whether diabetic effects of toxic metals can be mitigated by essential metals and, if so, the optimal body levels of essential metals that could reduce T2D risk from toxic metals. The Jinchang Metal Cohort Study is the only large prospectively study specifically designed to investigate the impact of metal exposures on cardiometabolic diseases. The study results will clarify the role of metals exposure as a modifiable risk factor for T2D at levels relevant to both the US and China, and will help to establish intervention strategies to improve cardiometabolic outcomes in human populations.